Average actuarial rate has been extending with the progress of medical sciences and technology, and senile dementia is now becoming a serious problem not only for family members including the patient but also for social structure. The existing drugs have been effective only for complicated symptoms and related diseases of senile dementia, and new drugs effective for the essential pathology are required.
Prolyl endopeptidase (EC 3.4.21.25) is an enzyme that selectively cleaves the carboxyl site of proline in peptides containing proline both in vitro and in vivo conditions, and degrades and inactivates neural peptide, vasopressin which is presumed to participate in mnemonic function [Nippon Nogeikagaku Kaishi, 58, 1147-1154 (1984)]. Thus the prolyl endopeptidase inhibitor is expected to exhibit anti-dementia activity and a variety of synthetic inhibitors have been reported to exhibit anti-amnestic effects in experimental studies in rats and mice [J. Pharmacobio-Dyn., 10, 730-735 (1987)]. Recently, a relationship between Alzheimer's disease type dementia and prolyl endopeptidase has attracted attention and a significant elevation of the enzyme level in the brain of patients [Experientia, 46, 94-97 (1990)], relationship to the C-terminal cleavage of A4(.beta.)-amyloid protein [FEBS LETTERS, 260, 131-134 (1990)] and effect of substance P which can be degraded by prolyl endopeptidase on the nerve degeneration caused by .beta.-protein [Proc. Natl. Acad. Sci., 88, 7248-7251 (1991)] have been reported. These findings intensified the expectation to prolyl endopeptidase inhibitor as an anti-amnestic agent. Particularly, the majority of existing synthetic drugs having similar chemical structures elucidated the structure-activity relationship in the inhibitors [Agric. Biol. Chem., 55, 37-43 (1991)]. Their activity, absorption, excretion and stability within living body have been established. On the other hand, inhibitors obtained from natural resources such as cultured Actinomycetes are expected to have unique and different structures from those of synthetic compounds, and advantages in the inhibitory activity, absorption, excretion and stability are awaited.
Furthermore, an emergent and definitive treatment of AIDS is required. There is no established treatment despite its high mortality rate and many countries including United States are concerned over serious social problems. At present , azidothymidine (AZT) has been used, but it also has potent adverse effects such as suppression of bone marrow, and drugs with a more direct action and less toxicity are desired. A recent experiment using a synthetic prolyl endopeptidase inhibitor found a particular relationship between the inhibitory activity of prolyl endopeptidase and an inhibitory activity on syncytium formation which is characteristic of the intercellular infection of HIV. Thus a new route for the development of new antiviral drugs based on the new mechanisms is expected [Japan Unexamined Patent Publication No. 124818 (1990)].